This invention is generally in the area of a transgenic animal model that is characterized by chronic heart failure (“CHF”) and which can survive an infarction caused by diet-induced coronary atherosclerosis. The animal model is useful to study CHF and treatments for chronic heart failure and coronary atherosclerosis regression.
Coronary atherosclerosis refers to the hardening and narrowing of the coronary arteries. The coronary arteries supply the blood that carries oxygen and nutrients to the heart muscle. When coronary arteries are narrowed or blocked by atherosclerosis, they cannot deliver an adequate amount of blood to the heart muscle. Disease caused by the lack of blood supply to heart muscle is called coronary heart disease (CHD). Coronary heart diseases is characterized by heart attacks, sudden unexpected death, chest pain, abnormal heart rhythms, and heart failure due to weakening of the heart muscle.
Chronic heart failure is the most common medical condition afflicting the western world. The major cause of CHF is myocardial infarction or the death of heart muscle during a heart attack, caused by coronary atherosclerosis. One of the risk factors for developing coronary atherosclerosis is elevated blood cholesterol. As blood cholesterol rises, so does risk of coronary heart disease and heart failure. When other risk factors (such as high blood pressure and tobacco smoke) are present, this risk increases even more. A person's cholesterol level is also affected by age, sex, heredity and diet. Cholesterol is vital for healthy cells. It is so important that the body does not rely on a dietary source, but produces its own cholesterol. However, if the body accumulates too much cholesterol, the cholesterol will deposit on the walls of arteries, which can damage or block the arteries, and cause a heart attack.
Excess cholesterol is produced when the diet is rich in saturated fats. An animal model for coronary heart disease (Apoeh/hSRB1−/− mice) is described in Zhang, et al., Circulation 111(25):3457-64 (2005) and WO 2005/011494. Apoeh/hSRB1−/− mice have slightly elevated blood cholesterol levels when fed a normal low fat diet, but do not develop coronary atherosclerosis or heart disease. However, when fed a diet rich in fat and cholesterol, Apoeh/hSRB1−/− mice develop very high blood cholesterol levels because of their low amounts of Arg61 apolipoproprotein E (ApoE) in the blood. High blood cholesterol levels rapidly cause occlusive coronary atherosclerosis in these mice, and they are subject to sudden death from severe heart failure caused by myocardial infarctions within 35 days of initiating the high cholesterol diet.
Myocardial infraction is currently treated by restoring blood flow in the heart by the placement of a drug eluting stent in the obstructed coronary artery or by coronary artery bypass surgery, alone or in combination with drugs that increase blood flow and inhibit platelet aggregation. However, despite restoration of blood flow, the heart remains damaged and, depending on the severity of the original heart attack, CHF results, resulting in reduced quality of life, including morbidity.
At the moment, there are very few technical solutions to significantly improve heart function in individuals with CHF. A major reason for the lack of treatments is the lack of reliable animal models that suffer from human-like CHF caused by myocardial infarction during a heart attack. A limitation of the coronary heart disease model described in WO 2005/011494 is the inability of the animals to recover from the coronary heart failure. Survival of the animals in WO 2005/011494 goes from 100% to 50%, ultimately reaching 0% by 45 days. An ideal animal model for CHF would be able to recover from myocardial infarctions caused by the blockage of coronary arteries by atherosclerosis, and develop the features characteristic of CHF. Such a model would provide a unique platform for scientists to develop new treatments for chronic heart failure in humans. Such a model would also be an ideal model for coronary atherosclerosis regression.
It is therefore an object of the present invention to produce an animal model for CHF and coronary atherosclerosis regression.
It is a further object of the present invention to use the CHF model to study the progression of CHF and test the effects of potential drugs and therapies to promote the growth of new blood vessels or heart muscle.
It is still another object of the invention to use the CHF model to screen for therapeutic compounds that could accelerate coronary atherosclerosis regression.